Lithium alleviates neurotoxic prion peptide-induced synaptic damage and neuronal death partially by the upregulation of nuclear target REST and the restoration of Wnt signaling

Neuropharmacology. 2017 Sep 1;123:332-348. doi: 10.1016/j.neuropharm.2017.05.021. Epub 2017 May 22.

Abstract

Prion diseases are a group of infectious neurodegenerative diseases characterized by multiple neuropathological hallmarks, including accumulation of PrPSc, synaptic damage, and neuronal death. We previously reported that the repressor element 1-silencing transcription factor (REST), a novel neuroprotective marker in neurodegeneration, protects neurons against neurotoxic peptide (PrP106-126)-induced neurotoxicity, but fails to maintain survival following prolonged exposure to PrP106-126. Because Wnt signaling partially induces REST and is activated by lithium, we investigated the effects of lithium on REST in prion diseases. Lithium restores nuclear expression of REST, which is essential for regulating survival proteins. Lithium also mimics neuroprotective functions when REST is blocked, and these beneficial effects are additive with REST overexpression under physiological conditions. Reciprocally, under PrP106-126-stimulated pathological conditions, REST plays a critical role in the neuroprotective mechanisms of lithium treatment. Although lithium recovers Wnt signaling by inhibiting glycogen synthase kinase-3β and stabilizing β-catenin, restores survival associated proteins after exposure to PrP106-126 in primary cortical neurons. Knockdown of REST significantly suppresses the neuroprotective function of lithium. Conversely, overexpression of REST partially recovers its actions. Notably, lithium directly alleviates PrP106-126-induced synaptic damage and neuronal cell death by preventing changes in presynaptic and postsynaptic marker proteins and promoting survival pathways also partially via the expression of REST. Our results suggest that REST acts as a novel and important nuclear target for lithium. We hypothesize that PrP106-126-stimulated neurotoxicity induces Wnt signaling dysfunction and lithium mimics this signaling cascade, suggesting that lithium should be considered as a potential therapeutic agent against prion diseases.

Keywords: Lithium treatment; Neuroprotection; Prion diseases; REST; Wnt signaling.

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Lithium Chloride / pharmacology*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Peptide Fragments / toxicity
  • Prion Diseases / drug therapy*
  • Prion Diseases / metabolism
  • Prion Diseases / pathology
  • Prions / toxicity
  • Rats, Sprague-Dawley
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Synapses / drug effects
  • Synapses / metabolism
  • Synapses / pathology
  • Up-Regulation / drug effects
  • Wnt Signaling Pathway / drug effects*
  • Wnt Signaling Pathway / physiology
  • beta Catenin / metabolism

Substances

  • Neuroprotective Agents
  • Peptide Fragments
  • Prions
  • RE1-silencing transcription factor
  • Repressor Proteins
  • beta Catenin
  • prion protein (106-126)
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Lithium Chloride